JBIC Journal of Biological Inorganic Chemistry, 2015, Vol.20(5), p.841(13)
Byline: Gilles Berger (1), Luca Fusaro (2), Michel Luhmer (2), Joanna Czapla-Masztafiak (3), Ewelina Lipiec (3), Jakub Szlachetko (4,5), Yves Kayser (4), Daniel L. A. Fernandes (6), Jacinto Sa (6,7), Francois Dufrasne (1), Sophie Bombard (8) Keywords: Cancer; Platinum; G-quadruplex; Conceptual DFT; RXES Abstract: The structure--activity relationships of chiral 1,2-diaminophenylalkane platinum(II) anticancer derivatives are studied, including interactions with telomeric- and genomic-like DNA sequences, the pKa of their diaqua species, structural properties obtained from DFT calculations and resonant X-ray emission spectroscopy. The binding modes of the compounds to telomeric sequences were elucidated, showing no major differences with conventional cis-platinum(II) complexes like cisplatin, supporting that the cis-square planar geometry governs the binding of small Pt(II) complexes to G4 structures. Double-stranded DNA platination kinetics and acid--base constants of the diaqua species of the compounds were measured and compared, highlighting a strong steric dependence of the DNA-binding kinetics, but independent to stereoisomerism. Structural features of the compounds are discussed on the basis of dispersion-corrected DFT, showing that the most active series presents conformers for which the platinum atom is well devoid of steric hindrance. If reactivity indices derived from conceptual DFT do not show evidences for different reactivity between the compounds, RXES experiments provide new insight into the availability of platinum orbitals for binding to nucleophiles. Author Affiliation: (1) Laboratoire de Chimie Pharmaceutique Organique, Universite Libre de Bruxelles, Campus Plaine CP205/5, Bd du Triomphe, 1050, Brussels, Belgium (2) Laboratoire de Resonance Magnetique Nucleaire Haute Resolution, Universite Libre de Bruxelles (ULB), Avenue F.D. Roosevelt 50, CP160/08, 1050, Brussels, Belgium (3) The Henryk Niewodniczanski Institute of Nuclear Physics, Polish Academy of Sciences, Krakow, Poland (4) Paul Scherrer Institute (PSI), Villigen, Switzerland (5) Institute of Physics, Jan Kochanowski University in Kielce, Kielce, Poland (6) Angstrom Laboratory, Department of Chemistry, Uppsala University, Uppsala, Sweden (7) Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland (8) Homeostasie Cellulaire et Cancer, UMR-S INSERM 1007, Universite Paris Descartes, 45 rue des Saint-Peres, 75006, Paris, France Article History: Registration Date: 07/05/2015 Received Date: 02/04/2015 Accepted Date: 03/05/2015 Online Date: 16/05/2015 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s00775-015-1270-6) contains supplementary material, which is available to authorized users.
Nuclear Physics ; Cancer Treatment ; Stereoisomers
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